Morphogens are proteins, peptides, complex lipids, carbohydrates, or combinations of the above that have a role in cell, tissue and organ development. The process of tissue and organ development, either embryonic or tissue regeneration and renewal, involves a carefully orchestrated spatially and temporally orchestrated proliferation and differentiation of pleuripotential stem cells to progenitor cells that then differentiate into specific cell lineages. The specific cell lineages progress to the development of the specific complex organ systems as dictated by changing environmental cues or signals, sometimes referred to as morphogens or growth factors. The family of proteins known as hedgehog are protein morphogens. In mammals, the known hedgehog proteins include sonic hedgehog (Shh), indian hedgehog (Ihh), and desert hedgehog (Dhh). Shh has generally been found to be involved in signaling in the development of the nervous system, Ihh in limb development, chondryocyte and cartilage differentiation, and Dhh in spermatogenesis.
For example, Shh is representative of hedgehog morphogens. The bioactive signaling form (morphogen) of Shh is a protein of 18 kDA modified by the covalent attachment of cholesterol. Shh is formed from a protein precursor of 43 kDA by autoproteolysis and attachment of cholesterol by cholesterol transferase activity encoded along with the autoprotease activity in the carboxyl terminal domain of the 43 kDA precursor protein of Shh. As is typical of morphogens that act on receptors on or within their target cells, Shh acts on the cell surface receptors known as patched and smoothened, activates a signaling cascade resulting in the activation of DNA-binding transcription factors, in turn resulting in the transcriptional expression of the set of genes required to define the specific phenotype of the cells at a given stage of development. Also typical of morphogens, the cellular responses to Shh are determined by its particular ambient concentration with a concentration gradient, and the prior association of the target cells with regard to exposure to preceding morphogens and the particular time within the developmental program.
In pancreas development, Shh plays an important role in early development, in which it is the absence of Shh that is permissive for early pancreas development (Hebrok et al., 1998, Genes and Dev. 12:1705; Apelqvist et al., 1997, Curr. Biol. 7:801). It has been shown that for the patterned epithelium of the foregut tube of the chick embryo to bud into pancreatic anlages Shh must be absent (Hebrok et al., 1998, supra). It has also been shown that early overexpression of Shh in transgenic mice results in a failure of early pancreas development and a marked dysmorphogenesis in the foregut region (Apelqvist et al., 1997, supra).